3. HISTORY
In 1967- Tomisaku Kawasaki reports a case series of 50 patients
and concluded clinical criteria for diagnosis
1974- english language report of Kawasaki disease by Kawasaki
1976- first series of american patients was reported
1977- Landing and Larson establish Kawasaki disease and PAN
are pathologicallhy indistinguishable
1988- AAP endorses high dose IVIG and ASA as recommended
therapy for Kawasaki disease
4. INTRODUCTION
Kawasaki disease (KD) is an
acute, self-limited febrile
illness of unknown cause that
predominantly affects children
<5 years of age.
Vasculitis of medium sized
vessels
Aka- Mucocutaneous lymph node
syndrome or infantile PA N
MCC acquired heart disease in
developed nation
5. EPIDEMIOLOGY
The incidence was highest among Asians and Pacific Islanders (30.3
per 100 000 children <5 years of age)
Incidence in Japan- 210/100000 children <5 yrs
Male : female ratio- 1.5:1
Recurrence rate- 3-5% with highest in first 2 yrs after index episode
Genetic predisposition- 2.1 % risk in sibling
Most common in winter and spring in US , no such association in
tropics
A/W perinatal exposure like older maternal age, GBS infection,
hospitalisation in infancy
The case fatality rate is <0.1% in Japan
6. GENETICS
single-nucleotide polymorphisms in 6 genes or gene regions:
FcγR2a, caspase 3 (CASP3), human leukocyte antigen class II,
Bcell lymphoid kinase (BLK), inositol 1,4,5-trisphosphate
kinase-C (ITPKC), and CD40
Genetic variations in TGFb gene signalling pathway is a/w risk of
coronary anurysms
Risk and response to treatment is determined by genetic factors
7. PATHOGENESIS
Immunologically mediated event
Infection with a RNA virus which cause intracytoplasmic
inclusion bodies could be a cause
Activation of innate immune system is an early event
Fever cessation is associated with expansion of regulatory T cells
Self limited course and less risk of recurrence throws evidence to
activation of memory B cells
8. PATHOLOGY
Systemic inflammtion in all medium sized arteries
multiple organ and tissue involvement
hepatitis, gastroenteritis, meningitis, interstitial
pneuminia, pancarditis, pyuria, lymphadenopathy
9. PATHOLOGY
KD arteriopathy has 3 pathological process
Stage 1- necrotising arteritis with neutrophilic sequestration
first 2 weeks of fever onset
destroys arterial wall aneurysms
Stage 2- subacute or chronic vasculitis
infiltration of lymphocytes , plasma cells and eosinophils with
few macrophages
begins in 2 weeks , continues for months to yrs
Stage 3- luminal myofibroblastic proliferation (LMP)
medial smooth muscle cell–derived myofibroblastic process
progressive arterial stenosis
begins in first 2 weeks and persists for months to years
10. Pathological outcome depends on the severity of coronary artery
damage
Mildly dilated artery can regain its original structure
Giant saccular aneurysms may rupture or thrombus can canalise
or calcify
Fusiform aneurysms with preserved media cause LMP and later
stenose
Pericarditis and myocarditis results from acute or subacute
inflammation
11. DIAGNOSIS
Fever of atleast 5 days + any 4 out of the following 5 features
Erythema and cracking of lips, strawberry tongue, and/or erythema
of oral and pharyngeal mucosa
Bilateral bulbar conjunctival injection without exudate
Rash: maculopapular, diffuse erythroderma, or erythema
multiforme-like
Erythema and edema of the hands and feet in acute phase and/or
periungual desquamation in subacute phase
Cervical lymphadenopathy (≥1.5 cm diameter), usually unilateral
Patients who meet the case definition based on principal clinical
findings -complete KD/ typical KD
Patients who do not have sufficient principal clinical findings -
incomplete KD /atypical KD
12. Fever: high spiking with remittant nature
lasts for 1-3 weeks
resolves within 36 hrs of IVIG infusion- if not resistance
Extremity changes:
Acute: erythema of palms and soles and painful induration of
hands and feet
Chronic : desquamation of fingers and toes to involve palms and
soles
Beus lines appears over nails
Rash: diffuse maculopapular rash appears within 5days of fever
extensive and primarily involves trunk and extremities
sometimes groin
13. Conjunctivitis: bilateral bulbar non-exudative conjunctival
injection sparing the limbus
Oral mucosa: changes of the lips and oral cavity include (1)
erythema, dryness, fissuring, peeling, cracking, and bleeding
of the lips; (2) a “strawberry tongue,” with erythema and
prominent fungiform papillae; and (3) diffuse erythema of the
oropharyngeal mucosa.
Cervical lymphadenopathy:
Lymph node swelling is usually unilateral, ≥1.5 cm in diameter,
Isolated Cx lymphadenopathy- USG and CT differentiates it from
bacterial lymphadenitis
14. CVS- myocarditis, pericarditis, valve regurgitation and shock
coronary artery abnormaliities
aneurysms of non coronary medium sized vessels
aortic root enlargement and
peripheral gangrene
Resp: Pulmonary nodules
peribronchial and interstitial nodules
Musculoskeletal: arthritis and arthralgia
Gastrointestinal: diarrhea, vomiting ,pain abdomen
hepatitis, GB hydrops, pancreatitis
Nervous : irritability , SNHL, facial N palsy , aseptic meningitis
GUT: urethritis. Hydrocele
Others: desquamating rash in groin, retropharyngeal phlegmon,
erythema nd induration in BCG site
15. DD- Measles
viral infection –adeno
Streptococcal and staphylococcal toxin mediated disease
Drug hypersensitivity reactions
Systemic JIA
Rickettseal infections
leptospirosis
Incomplete KD:
• In any child (esp infant)with prolonged unexplained fever with
one or more principle clinical finding and compatile laboratory
and echocardiographic findings
16. When to suspect KD....
• Infants <6 months old with prolonged fever and irritability
• Infants with prolonged fever and unexplained aseptic
meningitis
• Infants or children with prolonged fever and unexplained or
culture-negative shock
• Infants or children with prolonged fever and cervical
lymphadenitis unresponsive to antibiotic therapy
• Infants or children with prolonged fever and retropharyngeal
or parapharyngeal phlegmon unresponsive to antibiotic
therapy
17.
18. Laboratory tests:
• Leucocytosis with granulocytosis
• Anemia is normochromic and normocytic
• ESR andCRP- elevated
CRP normalizes more quickly than the ESR
ESR increases after IVIG thearpy
Decreased ESR with severe clinical symptoms s/o DIC
• Thrombocytosis – seen in 2 nd week and peaks in 3rd week and
resolves by 4-6 th week
thrombocytopenia in acute phase DIC
• Mild to moderate elevations in serum transaminases
• Hypoalbuminemia
• Urinanalysis- sterile pyuria
• CSF study- pleocytosis
19. CVS findings
CLINICAL:
The pericardium, myocardium, endocardium including valves, and the
coronary arteries all may be inflamed
Tachycardia , hyperdynamic precordium, innocent systolic murmur,
gallop rhythm.
Pericardial rub in case of tamponade
Valvar dysfunction occurs in ≈25% of patients mc mitral valve
PSM due to MR and diastolic murmur due to AR may be heard
ECG:
SA and AV node functional abnormalities
prolonged PR interval
nonspecific ST and T-wave changes
low voltage if there is myocardial or pericardial involvement
20. CV COMPLICATIONS
CV collapse:
Seen in 5% of cases
Septic shock must be ruled out
Children with shock presentation appear to be at higher risk of
IVIG resistance, coronary artery abnormalities, MR, and
prolonged myocardial dysfunction.
Myocardial dysfunction:
Develops early and transient
Improves rapidly as the inflammatory process results from
interstitial edema and inflammation and only rarely from
myocardial cell necrosis
Asso with ventricular ectopy
21. Valvular and aortic abnormalities:
MR is seen in 25% of KD
Asso with pancarditis
Mild to moderate in severity and is transient
AR is less common (<1%)
AR seen in asso with aortic root dialatation
Aotic root dilatation occurs in 10% of cases
Coronary artery abnormalities:
Specific diagnostic criteria for incomplete KD
Ranges from dilatation to aneurysms, proximal to distal
Majority have dilatation only with z score of 2-2.5, resolve sin 4-
8 weeks
Giant aneurysms can cause ischemia due to thrombosis or rupture
Other arterial involvement:
22. EVALUATION OF CARDIOVASCULAR
ABNORMALITIES
Echocardiography:
Noninvasive and has a high sensitivity and specificity
Initial echo must be performed at the time of diagnosis
Initial study is always normal in 1st week and act as baseline for
further follow up
Using high frequency transducer
In the order of frequency:
proximal LAD and proximal RCA > LMCA >left circumflex >
distal RCA > junction between the RCA and posterior
descending coronary artery
23. Qualitative and quantitative assessment:
Evaluation of coronaries – with internal diameter
Exclude branching points
Identify the number and location of thrombus
Types – saccular, fusiform and ectatic
Japanese guidelines- classify according to absolute and relative
internal diameter
< 5 yrs >5 yrs
Small <4mm 1.5 times
Med >4 , </= 8mm 1.5 to 4 times
Large >8mm >4 times
24. Defining abnormality-
Z score of >2.5 in one coronary is normal in 0.6 % and >3 in
0.1%
Z score more than 2.5 in two coronaries (LAD and RCA)not
normal
Anatomical variation of LMCA exist
Z-Score Classification :
1. No involvement: Always <2
2. Dilation only: 2 to <2.5; or if initially <2, a decrease in Z
score during follow-up ≥1
3. Small aneurysm: ≥2.5 to <5
4. Medium aneurysm: ≥5 to <10, and absolute dimension <8 mm
5. Large or giant aneurysm: ≥10, or absolute dimension ≥8 mm
25. Assess ventricular function and ejection fraction
Assess systolic and diastolic dimensions of ventricle and regional wall
motion abnormalities
Assessment of aortic root:
Root dilatation >2 z score in 10% KD
Look for pericardial effusion and valvular regurgitation
For uncomplicated patients, echo should be repeated both within 1 to 2
weeks and 4 to 6 weeks after treatment
For evolving CAD , echo must be repeated twice per week till its size
stops progressing to contain a thrombus
With thrombosis echo is indicated once weekly for first 45 days and
monthly till 3 months
Other imaging modalities:
TEE
Invasive angiography
CTA
CMRI
26. TREATMENT OF ACUTE ILLNESS
From onset of acute illness to resolution of acute systemic
inflammation when coronaries stop expanding
Single high dose IVIG plus ASA
Patient selection:
With complete KD and incomplete KD
IVIG should be given once diagnosis is made, within 10 days of
onset of illness
IVIG should be given to children presenting after 10th day of
illness if
a) persistent unexplained fever
b) elevated CRP or ESR
c) coronary dimensions z score more than 2.5
d) recurrent KD
27. IVIG:
modulation of cytokine production,
neutralization of toxins or other pathogenic agents
augmentation of regulatory T-cell activity
suppression of antibody synthesis and provision of
antiidiotypic antibodies
Lowers the incidence of coronary artery abnormalities
2 g/kg as a single infusion, usually given over 10 to 12 hours,
together with ASA
S/E: hemolytic anemia, aseptic meningitis (without any sequela)
defer all live vaccines for next 11 months of administartion
28. ASA:
High dose act as antiinflammatory and low dose act as
antiplatelet
Does not lower the incidence of CA anbormality
Dose: 80-100mg/kg/d every 6 th hourly
High dose is given for 48-72hrs of afebrile period or 14 days of
illness
Low-dose ASA (3 to 5 mg/kg/d) is given after that and continued
until the patient has no evidence of coronary changes by 6 to 8
weeks after onset of illness
If they develop CA abnormality it is further continued
S/E- Reye syndrome- develops influenza or varicella while on
high dose ASA
Alternative antiplatelet agent must be given and immunise the
child
29. ADJUNCT THERAPY
For those at the risk of coronary artery abnormality
Corticosteroid:
Lower incidence of coronary artery abnormalities
Lower risk of retreatment
Rapid resolution of fever and more rapid decrease in CRP
levels
Lower risk of IVIG resistance
Regimen: IVIG (2 g/kg for 1 day) + ASA (30 mg/kg/d) plus
intravenous prednisolone (2 mg/kg/d) for 5 days followed by
an oral taper over weeks
30. Infliximab:
Anti TNF alpha monoclonal antibody
Halts inflammation in resistant KD
Decrease in incidence of IVIG resistance
Rapid reduction in inflammatory parameters
Decrease the rate of IVIG reactions
Dose: 5mg/kg/dose iv over 2 hrs
Etanercept: (soluble TNF receptor)
Administer subcutaneously after IVIG and repeat at 1 and 2
weeks later
31. IVIG Resistance
Recrudescent or persistent fever at least 36 hours after the end of the
IVIG infusion
Incidence- 10-20%
Polymorphism in Fc gama receptor
Treatment of IVIG resistance:
1) IVIG: Second infusion- 2 g/kg/dose
2) IVIG + prednisolone: IVIG 2 g/kg IV + pred 2 mg/kg/dose IV
divided every 8 h until afebrile, then orally until CRP normalise,
then taper over 2–3 wk
3) Cyclosporine- IV: 3 mg/kg/d, divided every 12 h PO: 4–8 mg/kg/d
divided every 12 h
4) Anakinra- 2–6 mg/kg /d given by subcutaneous injection
5) Cyclophosphamide - 2 mg/kg/dose
6) Plasma exchange
32. Cyclospsorine:
Specific inhibitor of calcineurin
NFAT-calcineurin calcium signaling pathway contribute to
inflammatory action in KD
Dose- IV 3 mg/kg/d, divided every 12 h, PO: 4–8 mg/kg/d
divided every 12 h
Once the patient is afebrile + clinically improving + CRP is ≤1.0
mg/dL, or after 2 weeks of therapy, the dose can be tapered by
10% of the initial dose every 3 days and discontinued when
the dose has reached 1 mg/kg/d
Anakinra- IL-1 antagonist
Plasma exchange- in case medical therapy fails
33. Treatment of acute myocardial dysfunction:
KDSS results from interstitial edema and cellular infiltration
KDSS – hypotension and shock requiring the initiation of volume
expanders, the infusion of vasoactive agents, or transfer to
intensive care units
Mechanism
• Release of endogenous molecules that mediate a decrease in
peripheral vascular resistance (distributive)
• myocardial dysfunction from myocarditis with or without
myocardial ischemia(cardiogenic)
• capillary leakage
Treatment: fluids + ionotropes + IVIG
34. Treatment and prevention of coronary artery aneurysm
Thrombocytosis , increased platelet adhesion, inflammation, and
endothelial dysfunction, together with abnormal flow
conditions through areas of severe dilation.
For small aneurysm: monotherapy with low-dose ASA therapy is
sufficient for prophylaxis of thrombosis.
For mod aneurysm: ASA therapy combined with a
thienopyridine (eg, clopidogrel)
For giant aneurysm: “triple therapy” with ASA, a second
antiplatelet agent, and anticoagulation with warfarin (INR- 2 to
3)or LMWH
Anticoagulation in infants with LMWH
Transition from LMWH to warfarin once aneurysms stopped
expanding and the patient is stable
35. Treatment :
Goals: reestablishing coronary artery patency and flow, salvaging
myocardium, and improving survival
By thrombolytic therapy or mechanical restoration of coronary
artery flow by cardiac catheterisation
Thrombolysis by tPA - in infants and children
Dose- 0.5mg/kg/hr over 6hrs
Along with low dose aspirin and low dose heparin
Monitor coagulation parameters
Maintain fibrinogen level more than 100mg/dl
Maintain platelet count more than 50000
After tPA increase heparin dose and assess thrombus by echo
If rebound increase in thrombus size or same size of thrombus ,
then low dose thrombolytic with abciximab
36. Coronary artery events (thrombosis, stenosis, intervention, MI,
death)
Late development or increases in size of aneurysms have been
reported in case reports.
Late-onset valvulitis of the mitral and aortic valves (rare)and
may require valve replacement.
MR can occur after the acute stage from myocardial ischemia.
AR in KD is usually associated with aortic root dilation and
apparent early in the course of the disease
Long-term myocardial dysfunction, resulting from primary
myocardial insult at the time of acute KD
Premature ventricular contractions and ventricular tachycardia
are common
37. LONGTERM MANAGEMENT
Begins at the end of acute illness ie, 4-6 weeks after fever onset
Goal: prevent thrombosis and MI
Medically – thromboprophylaxis and surveillance for coronary
artery stenosis and obstruction
Intervention – coronary revascularisation by transcatheter or
coronary bypass graft or cardiac transplantation
39. No involvement:
Follow up to 1yr
Low dose ASA for upto 4-6wks and discontinue later
Check BP, lipid profile, dietary assessment atleast once after 1 yr
No additional medical therapy
No restriction on physical activity
Dialtation only(z score>/= 2 < 2.5 or decrease in z score during
follow up)
Lumen dimension returned to normal by 4-6 wks F/U upto 1yr
Dimension not returned to normal follow up to 12 months
If dilatation present at 1 yr continue follow up every 2-5 yrs
Low dose ASA for upto 4-6 wks and discontinue later
40. No restriction on physical activity
Counseling regarding healthy lifestyle and activity promotion at
every visit
Small aneurysm z score >/=2.5 <5
a) Current or persistant
Patient should be seen at 4-6 weeks after onset, then follow up at
6 months and 1 yr and annually later
Assess for inducible MI at every 2-3 yrs if symptoms o f MI or
dysfunction present
Imaging with angio and CT every 3-5 yrs
Check BP, lipid profile, dietary assessment atleast once after 1yr
Low dose ASA or clopidogrel can be given
Empirical statin therapy can be considered
No restriction on physical activity
41. b) Regression to normal Z score or dilatation
Regular follow up every 1-3 yrs
Assess for inducible MI every 2-3 yrs if symptomatic
Additional imaging if evidence for inducible MI
Medium aneurysms
a) Current or persistent
Review at 4-6 weeks, then 3 Mo, 6Mo and at 1 yr. Follow up
assessment every 6-12 months later
Assess for inducible myocardial ischemia every 1-3 yr
Further imaging with angio every 2-5 yrs
Counsel regarding healthy life style and activity promotion
Medications:
Low dose ASA
42. Empirical statin therapy
Use of alternative antiplatelet agent can be consisdered
Dual antiplatelet therapy can be considered
Perform FLP ,BMI dietary assessment annually
Use of anticoagulant is not recommended
L/F coronary artery characteristics to intensify thromboprophylaxis
Restricted physical activity- inducible MI testing before competitive
sports and also for those on dual therapy
Discourage the use of OCPs as contraceptive methods
b) Regression to small aneurysm:
Annual follow up assessment
Assess for inducible MI every 2-3 yrs
Additional imaging every 3-5 yrs
Medications:
43. Low dose ASA
Low dose statin therapy
Dual anti platelet therapy may be considered
Normal activity no restriction, competitive sport after MI test
c) Regression to normal z score or dilatation
Follow up assessment every 1-2 yrs
Assess for inducible MI every 2-4 yrs and no further imaging
CV risk assessment every 2 yrs
Medication : Statins, ASA, alternative antiplatelet and no
additional antiplatelet
No limitation in daily activity, competitive sports after inducible
MI test
44. Large Aneurysms:
a)Current or persistent:
Assess patients at 1, 2, 3, 6, 9, and 12 months after the episode of
acute KD in the first year and every 3 to 6 months thereafter
Assess for inducible MI every 6-12 months
Further imaging every 1-5 yrs
CV risk assessment every 6-12 months
Medications:
Empirical statin and beta blocker
Low dose ASA
Additional antiplatelet therapy
Warfarin to be considered to achieve INR 2-3/ LMWH as an
alternative
45. b)Regression to medium aneurysm:
Assess every 6-12 months
Assess for inducible MI annually
Medications:
Use of statin and beta blocker is considered
Low dose aspirin
Anticoagulation is not indicated
c) Regression to small aneurysm or normal size:
Assessment is same
Medications:
Low dose aspirin and beta blocker
Beta blocker is not indicated if size normalise
No additional antiplatelet or anticoagulant
46. Revascularisation
Revascularization should be avoided in KD patients in the
acute/subacute phase of the illness with STEMI attributable to
acute thrombotic occlusion of an aneurysm
Adult patients with remote history of KD presenting with STEMI
should be referred emergently for coronary angiography
Revascularization should be performed in KD patients
a) with stable angina and high-risk coronary anatomy including
left main CAD, multivessel coronary disease with reduction in
LV function, multivessel coronary disease with diabetes
mellitus
b)non–ST-segment elevation and coronary anatomy amenable to
revascularization on coronary angiography
47. c) for patients with stable angina and symptoms refractory to
maximal medical therapy
d) patients with silent ischemia and ischemia involving >10% of
LV mass may be considered
CABG vs PCI
CABG is preferred to PCI in KD patients with left main CAD,
multivessel CAD with reduced LV function, multivessel CAD
with lesions not amenable to PCI, and multivessel CAD in
diabetic patients
PCI is preferred in patients with single-vessel or focal multivessel
disease amenable to PCI
CABG is preferred to PCI in older children and adults with KD
and multivessel involvement
48. Cardiac transplantation:
It is reasonable to consider cardiac transplantation for patients
with severe, irreversible myocardial dysfunction and coronary
artery lesions for which interventional catheterization
procedures or CABG are not feasible
